The long-term goal of this study is to elucidate the role of the endogenous system in cocaine addiction using positron emission tomography (PET) by correlating the effects of cocaine on mu opioid receptor binding and performance on cognitive tests of decision-making, memory, and risk assessment. Efforts to understand the factors that maintain prolonged abuse of cocaine have recently focused on the role of endogenous opioids and opioid receptors. PET provides an opportunity to measure dynamic changes in mu opioid receptor binding following cocaine administration in human cocaine addicts by the use of the mu- selective ligand, 11C-carfentanil. Preliminary results from this laboratory are promising: mu-opioid receptors in several brain regions are significantly increased in cocaine abusers and acute cocaine can change mu opioid receptor binding, in accord with results in experimental animals. Furthermore, the changes in mu opioid receptor binding we have observed are correlated with measures of euphoria and relapse. Thus, the specific aims of this proposal are to: 1) measure regional mu opioid receptor binding before and after cocaine administration in chronic cocaine users by PET imaging.; and 2) determine the relationships between regional mu opioid receptor binding before and after cocaine administration and parameters altered cognition and relapse. The proposed research design utilizes the noninvasive nature of PET to compare mu opioid receptors in cocaine addicts following chronic abuse, as well as correlating PET data with objective and subjective measures of cocaine abuse and response cocaine administration. The medical significance of this proposal is threefold: to further understanding of the mechanisms of cocaine reinforcement; to determine the relations between modulation of mu opioid receptor binding and cognition; and to improve our ability to identify patients likely to relapse following treatment for cocaine abuse.